West Nile virus (WNV) is a neurotropic virus well documented to require innate immunity, humoral immunity, as well as T-cell mediated immunity in order to generate effective protection and viral control. Due to the varied and complex nature of the immune responses generated in response to WNV infection, there are naturally complex and varied genetic networks involved in immunity to WNV as well, though to date, we lack a complete understanding of how host genetic diversity impacts the orchestration of immunity to virus infection. Thus, the goal of Project 4 is to use a systems immunology approach to identify candidate host genes and genetic networks that control regulation of adaptive immunity, as well as the interplay between innate and adaptive immunity, to West Nile virus infection, thereby providing us with a better understanding of how adaptive immunity to neurotropic viruses is regulated at the genetic level. In order to accomplish this goal, we plan to use the Collaborative Cross (CC) mice, a highly diverse recombinant inbred mouse panel designed to promote the identification and characterization of multiple interacting genes underlying complex phenotypes, such as host immunity to viral infection. The use of this unique genetic tool will therefore allow us to identify multiple immunoregulatory genes and genetic networks that control various aspects of WNV induced adaptive immunity, and in conjunction with Project 3, the goal of which is to identify genes regulating innate immunity to WNV, to link innate and adaptive immune networks in response to WNV. This will ultimately allow us to not only validate these targets in human systems, but also to generate more effective animal models of virus infection so that we can better simulate human diversity and make further discoveries that will allow us to create better vaccines and therapies for West Nile and other neuroinvasive viral diseases.